tbuckley/cabot-search huggingface dataset:
Pushing the boundaries of brain organoids to study Alzheimer’s disease
Authors: Jonas Cerneckis, Guojun Bu, Yanhong Shi
Journal: Trends in Molecular Medicine (2023)

Progression of Alzheimer's disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell-cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD.
Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial
Authors: John R Corboy, Robert J Fox, Ilya Kister, Gary R Cutter, Charity J Morgan, Rebecca Seale, Eric Engebretson, Tarah Gustafson, Aaron E Miller, Dennis Bourdette, Vijayshree Yadav, Andrew Goodman, Michael Racke, Robert Fallis, Carlo Tornatore, Myla Goldman, Meena Kannan, Subramaniam Sriram, Joseph Berger, Anne Cross, Kottil Rammohan, Zongqi Xia, Thomas Leist, Sharon Lynch, Eric Klawiter, Lilyana Amezcua, James Bowen
Journal: The Lancet Neurology (2023)
Frequency of euthanasia, factors associated with end-of-life practices, and quality of end-of-life care in patients with amyotrophic lateral sclerosis in the Netherlands: a population-based cohort study
Authors: Remko M van Eenennaam, Willeke Kruithof, Anita Beelen, Leonhard A Bakker, Ruben P A van Eijk, Maud Maessen, Joost F Baardman, Johanna M A Visser-Meily, Jan H Veldink, Leonard H van den Berg
Journal: The Lancet Neurology (2023)
Substituted Judgment: How Accurate Are Proxy Predictions?
Authors: Allison B. Seckler, Diane E. Meier, Michael Mulvihill, Barbara E. Cammer Paris
Journal: Annals of Internal Medicine (1991)

Substituted judgment has been proposed as a method of promoting the autonomy of the mentally incapacitated patient, but little is known about the accuracy of surrogate decision makers in reflecting the true wishes of patients. In this study, surrogate decision makers' views (those of primary care providers and close family members) were compared with the decisions of currently competent chronically ill elderly patients, using a hypothetic cardiopulmonary resuscitation scenario under circumstances of current health and progressive dementia. Concordance between patients and their surrogates was evaluated by assessing percent agreement, kappa coefficient (for concordance beyond chance), and directionality of discrepant responses. Most patient respondents chose to be resuscitated in both scenarios. Although patients predicted that both their physicians (90%) and family members (87%) would accurately represent their wishes, neither family members nor physicians, in fact, were able to adequately predict patients' wishes in both scenarios (kappa ≤ 0.3 in all scenarios; percent agreement range, 59% to 88%). Few patients had ever discussed their resuscitation preferences with either their family member (16%) or their physician (7%). These results cast doubt on the usefulness of a strict substituted judgment standard as an approach to medical decision making for patients with diminished mental capacity.
Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins
Authors: Natalie DeForest, Babu Kavitha, Siqi Hu, Roi Isaac, Lynne Krohn, Minxian Wang, Xiaomi Du, Camila De Arruda Saldanha, Jenny Gylys, Edoardo Merli, Ruben Abagyan, Laeya Najmi, Viswanathan Mohan, Jason Flannick, Gina M Peloso, Philip L S M Gordts, Sven Heinz, Aimee M Deaton, Amit V Khera, Jerrold Olefsky, Venkatesan Radha, Amit R Majithia
Journal: Cell Genomics (2023)

Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding
Opioid and Methadone Use for Infants With Surgically Treated Necrotizing Enterocolitis
Authors: Olivia A. Keane, Abigail K. Zamora, Shadassa Ourshalimian, Elaa M. Mahdi, Ashley Y. Song, Eugene Kim, Ashwini Lakshmanan, Eugene S. Kim, Lorraine I. Kelley-Quon
Journal: JAMA Network Open (2023)

Importance Necrotizing enterocolitis (NEC) requiring surgical intervention is the most common reason for surgical procedures in preterm neonates. Opioids are used to manage postoperative pain, with some infants requiring methadone to treat physiologic opioid dependence or wean from nonmethadone opioid treatment during recovery. Objective To describe postoperative opioid use and methadone treatment for infants with surgically treated NEC and evaluate postoperative outcomes. Design, Setting, and Participants A cohort study of infants with surgically treated NEC admitted from January 1, 2013, to December 31, 2022, to 48 Children’s Hospital Association hospitals contributing data to the Pediatric Health Information System (PHIS) was performed. Infants who received methadone preoperatively, were aged 14 days or less at the time of the operation, had a congenital heart disease–related operation, or died within 90 days of the operation were excluded. Mixed-effects multivariable logistic regression was used to evaluate thresholds for duration of opioid use after the operation associated with methadone treatment and clinical outcomes associated with methadone use were enumerated. Exposure Postoperative administration of nonmethadone opioids. Main Outcomes and Measures Methadone use and postoperative length of stay, ventilator days, and total parenteral nutrition (TPN) days. Results Of the 2037 infants with surgically treated NEC identified, the median birth weight was 920 (IQR, 700.0-1479.5) g; 1204 were male (59.1%), 911 were White (44.7%), and 343 were Hispanic (16.8%). Infants received nonmethadone opioids for a median of 15 (IQR, 6-30) days after the operation and 231 received methadone (11.3%). The median first day of methadone use was postoperative day 18 (IQR, days 9-64) and continued for 28 days (IQR, 14-73). Compared with infants who received nonmethadone opioids for 1 to 5 days, infants receiving 16 to 21 days of opioids were most likely to receive methadone treatment (odds ratio, 11.45; 95% CI, 6.31-20.77). Methadone use was associated with 21.41 (95% CI, 10.81-32.02) more days of postoperative length of stay, 10.80 (95% CI, 3.63-17.98) more ventilator days, and 16.21 (95% CI, 6.34-26.10) more TPN days. Conclusions and Relevance In this cohort study of infants with surgically treated NEC, prolonged use of nonmethadone opioids after the operation was associated with an increased likelihood of methadone treatment and increased postoperative length of stay, ventilation, and TPN use. Optimizing postoperative pain management for infants requiring an operation may decrease the need for methadone treatment and improve health care use.
Pre-admission ambient air pollution and blood soot particles predict hospitalisation outcomes in COVID-19 patients
Authors: Stijn Vos, Elien De Waele, Pieter Goeminne, Esmée M. Bijnens, Eva Bongaerts, Dries S. Martens, Robert Malina, Marcel Ameloot, Karolien Dams, Annick De Weerdt, Geert Dewyspelaere, Rita Jacobs, Geert Mistiaen, Philippe Jorens, Tim S. Nawrot
Journal: European Respiratory Journal (2023)

Background Air pollution exposure is one of the major risk factors for aggravation of respiratory diseases. We investigated whether exposure to air pollution and accumulated black carbon (BC) particles in blood were associated with coronavirus disease 2019 (COVID-19) disease severity, including the risk for intensive care unit (ICU) admission and duration of hospitalisation. Methods From May 2020 until March 2021, 328 hospitalised COVID-19 patients (29% at intensive care) were recruited from two hospitals in Belgium. Daily exposure levels (from 2016 to 2019) for particulate matter with aerodynamic diameter &lt;2.5 µm and &lt;10 µm (PM 2.5 and PM 10 , respectively), nitrogen dioxide (NO 2 ) and BC were modelled using a high-resolution spatiotemporal model. Blood BC particles (internal exposure to nano-sized particles) were quantified using pulsed laser illumination. Primary clinical parameters and outcomes included duration of hospitalisation and risk of ICU admission. Results Independent of potential confounders, an interquartile range (IQR) increase in exposure in the week before admission was associated with increased duration of hospitalisation (PM 2.5 +4.13 (95% CI 0.74–7.53) days, PM 10 +4.04 (95% CI 1.24–6.83) days and NO 2 +4.54 (95% CI 1.53–7.54) days); similar effects were observed for long-term NO 2 and BC exposure on hospitalisation duration. These effect sizes for an IQR increase in air pollution on hospitalisation duration were equivalent to the effect of a 10-year increase in age on hospitalisation duration. Furthermore, for an IQR higher blood BC load, the OR for ICU admission was 1.33 (95% CI 1.07–1.65). Conclusions In hospitalised COVID-19 patients, higher pre-admission ambient air pollution and blood BC levels predicted adverse outcomes. Our findings imply that air pollution exposure influences COVID-19 severity and therefore the burden on medical care systems during the COVID-19 pandemic.
A Glimmer of Hope for an Orphan Disease
Authors: Marc G. Ghany
Journal: New England Journal of Medicine (2023)

Hepatitis D virus (HDV) is a small satellite virus that is present almost exclusively in persons with chronic hepatitis B virus (HBV) infection because of its dependence on HBV surface antigen (HBsAg) for transmission and infectivity. Among HBsAg-positive persons, approximately 5% are infected with HDV, which corresponds to approximately 12 million persons (95% confidence interval, 8.7 million to 18.7 million) worldwide.1 The estimated prevalence of HDV infection in the United States is low (0.11% of persons).2 Accordingly, chronic HDV infection qualifies for the Food and Drug Administration Orphan Drug Designation Program, a status that is typically granted for diseases that . . .
TGF-β1/SMAD3 Regulates Programmed Cell Death 5 That Suppresses Cardiac Fibrosis Post–Myocardial Infarction by Inhibiting HDAC3
Authors: Lin Weng, Jingjing Ye, Fenghe Yang, Shi Jia, Minghong Leng, Bo Jia, Chunling Xu, Yang Zhao, Ruxia Liu, Yufei Xiong, Yiqing Zhou, Junhui Zhao, Ming Zheng
Journal: Circulation Research (2023)

Progressive cardiac fibrosis leads to ventricular wall stiffness, cardiac dysfunction, and eventually heart failure, but the underlying mechanism remains unexplored. PDCD5 (programmed cell death 5) ubiquitously expresses in tissues, including the heart; however, the role of PDCD5 in cardiac fibrosis is largely unknown. Therefore, this study aims at exploring the possible role and underlying mechanisms of PDCD5 in the pathogenesis of cardiac fibrosis.PDCD5 levels were found to be elevated in the serum obtained from patients with cardiac fibrosis, in fibrotic mice heart tissues after myocardial infarction, and in cardiac fibroblasts stimulated by Ang II (angiotensin II)- or TGF-β1 (transforming growth factor-β1). Overexpression of PDCD5 in cardiac fibroblasts or treatment with PDCD5 protein reduced the expression of profibrogenic proteins in response to TGF-β1 stimulation, while knockdown of PDCD5 increased fibrotic responses. It has been demonstrated that SMAD3, a protein that is also known as mothers against decapentaplegic homolog 3, directly upregulated PDCD5 during cardiac fibrosis. Subsequently, the increased PDCD5 promoted HDAC3 (histone deacetylase 3) ubiquitination, thus, inhibiting HDAC3 to reduce fibrotic responses. Fibroblast-specific knock-in of PDCD5 in mice ameliorated cardiac fibrosis after myocardial infarction and enhanced cardiac function, and these protective effects were eliminated by AAV9-mediated HDAC3 overexpression.The findings of this study demonstrated that PDCD5 is upregulated by SMAD3 during cardiac fibrosis, which subsequently ameliorated progressive fibrosis and cardiac dysfunction through HDAC3 inhibition. Thus, this study suggests that PDCD5 functions as a negative feedback factor on fibrotic signaling pathways and might serve as a potential therapeutic target to suppress the progression of fibrotic responses.
The rate and pattern of fetal hemoglobin decline adjusted to sickle cell status of newborns in Dar es Salaam, Tanzania: A prospective cohort study
Authors: Salama Nyangasa, David Solomon, Belinda Njiro, Anab Faisal, Julie Makani, Siana Nkya
Journal: American Journal of Hematology (2023)

Foetal haemoglobin (%) and foetal cell (%) according to sickle cell status.
Considerations on the Management of Acute Postoperative Ischemia After Cardiac Surgery: A Scientific Statement From the American Heart Association
Authors: Mario Gaudino, George D. Dangas, Dominick J. Angiolillo, Jessica Brodt, Joanna Chikwe, Abe DeAnda, Irbaz Hameed, Mary L. Rodgers, Sigrid Sandner, Louise Y. Sun, Celina M. Yong
Journal: Circulation (2023)

Acute postoperative myocardial ischemia (PMI) after cardiac surgery is an infrequent event that can evolve rapidly and become a potentially life-threatening complication. Multiple factors are associated with acute PMI after cardiac surgery and may vary by the type of surgical procedure performed. Although the criteria defining nonprocedural myocardial ischemia are well established, there are no universally accepted criteria for the diagnosis of acute PMI. In addition, current evidence on the management of acute PMI after cardiac surgery is sparse and generally of low methodological quality. Once acute PMI is suspected, prompt diagnosis and treatment are imperative, and options range from conservative strategies to percutaneous coronary intervention and redo coronary artery bypass grafting. In this document, a multidisciplinary group including experts in cardiac surgery, cardiology, anesthesiology, and postoperative care summarizes the existing evidence on diagnosis and treatment of acute PMI and provides clinical guidance.
Mechanistic evaluation of the initial burst release of leuprolide from spray-dried PLGA microspheres
Authors: Richard Schutzman, Nian-Qiu Shi, Karl F. Olsen, Rose Ackermann, Jie Tang, Ya-Yuan Liu, Justin K.Y. Hong, Yan Wang, Bin Qin, Anna Schwendeman, Steven P. Schwendeman
Journal: Journal of Controlled Release (2023)
Dynamics of invasive pneumococcal disease in infants &lt; 2 years old following PCV7/13 implementation using two infant and a booster dose schedule: evidence for indirect protection of young infants, Israel, 2004 to 2019
Authors: Shalom Ben-Shimol, Bart Adriaan van der Beek, Meirav Mor, Orli Megged, Ron Dagan
Journal: Eurosurveillance (2023)

Background Pneumococcal conjugated vaccine (PCV)7 and PCV13 programmes started in Israel from July 2009 and November 2010 respectively, with a 2+1 schedule (one dose at 2 months old, one at 4 months old, and a booster dose at 12 months old). Thereafter, invasive pneumococcal disease (IPD) rates substantially declined in children. Uptake of all three doses in &lt; 2-year-olds since 2012 is &gt; 90%. For still incompletely vaccinated infants (≤ 12 months old), how well the PCV 2+1 programme shields from IPD is not fully resolved. Aim To assess the adequacy of protection conferred by the 2+1 schedule PCV vaccination programme, particularly among incompletely-vaccinated infants. Methods This was a population-based, prospective, nationwide active IPD surveillance study in Israel, 2004–2019, in children &lt; 24 months old. We estimated annual incidence rates (IR) of overall IPD, IPD caused by PCV13 serotypes (VT13), and non-PCV13 serotypes (NVT13). Annual IPD IRs were stratified by age: &lt; 4 months (receiving ≤ 1 dose), 4–6 months (immediately post dose 2), 7–12 months (a few months post dose 2), and 13–23 months (post dose 3). Late-PCV (2004–2008) to pre-PCV13 (2016–2019) mean annual IR ratios (IRRs) were calculated. Results 2,569 IPD episodes were recorded. VT13 decreased &gt; 90% in all age groups, while NVT13 seemed to increase. All-IPD rates declined in all age groups by 56–70%. The 2+1 schedule impact on 7–12-month-old infants (pre-booster) was similar to that on 13–23-month-old children (post booster), with PCV13 IPD reductions of 97% and 98%, respectively. Conclusions Indirect (herd) protection of infants, including &lt; 4 month-olds with ≤ 1 PCV dose, was achieved by the 2+1 PCV schedule programme which thus seems adequate.
Development of a Deep Learning Model for Retinal Hemorrhage Detection on Head Computed Tomography in Young Children
Authors: Fatma Gunturkun, Berna Bakir-Batu, Adeel Siddiqui, Karen Lakin, Mary E. Hoehn, Robert Vestal, Robert L. Davis, Nadeem I. Shafi
Journal: JAMA Network Open (2023)

Importance Abusive head trauma (AHT) in children is often missed in medical encounters, and retinal hemorrhage (RH) is considered strong evidence for AHT. Although head computed tomography (CT) is obtained routinely, all but exceptionally large RHs are undetectable on CT images in children. Objective To examine whether deep learning–based image analysis can detect RH on pediatric head CT. Design, Setting, and Participants This diagnostic study included 301 patients diagnosed with AHT who underwent head CT and dilated fundoscopic examinations at a quaternary care children’s hospital. The study assessed a deep learning model using axial slices from 218 segmented globes with RH and 384 globes without RH between May 1, 2007, and March 31, 2021. Two additional light gradient boosting machine (GBM) models were assessed: one that used demographic characteristics and common brain findings in AHT and another that combined the deep learning model’s risk prediction plus the same demographic characteristics and brain findings. Main Outcomes and Measures Sensitivity (recall), specificity, precision, accuracy, F1 score, and area under the curve (AUC) for each model predicting the presence or absence of RH in globes were assessed. Globe regions that influenced the deep learning model predictions were visualized in saliency maps. The contributions of demographic and standard CT features were assessed by Shapley additive explanation. Results The final study population included 301 patients (187 [62.1%] male; median [range] age, 4.6 [0.1-35.8] months). A total of 120 patients (39.9%) had RH on fundoscopic examinations. The deep learning model performed as follows: sensitivity, 79.6%; specificity, 79.2%; positive predictive value (precision), 68.6%; negative predictive value, 87.1%; accuracy, 79.3%; F1 score, 73.7%; and AUC, 0.83 (95% CI, 0.75-0.91). The AUCs were 0.80 (95% CI, 0.69-0.91) for the general light GBM model and 0.86 (95% CI, 0.79-0.93) for the combined light GBM model. Sensitivities of all models were similar, whereas the specificities of the deep learning and combined light GBM models were higher than those of the light GBM model. Conclusions and Relevance The findings of this diagnostic study indicate that a deep learning–based image analysis of globes on pediatric head CTs can predict the presence of RH. After prospective external validation, a deep learning model incorporated into CT image analysis software could calibrate clinical suspicion for AHT and provide decision support for which patients urgently need fundoscopic examinations.
Assessment of Homologous Recombination Deficiency in Ovarian Cancer
Authors: Vikas Garg, Amit M. Oza
Journal: Clinical Cancer Research (2023)

Summary Accurately assessing homologous recombination deficiency (HRD) to use as a predictive biomarker is an area of intense research in ovarian cancer. Validated assays have demonstrated utility in determining maintenance therapy following platinum sensitive chemotherapy. Novel functional assays promise the potential to reflect HRD in real time and predict response to PARP inhibitors. See related articles by Pikkusaari et al., p. 3110 and Blanc-Durand et al., p. 3124
<scp>Herpesvirus‐Bacteria</scp> pathogenic interaction in juvenile (aggressive) periodontitis. A novel etiologic concept of the disease
Authors: Jørgen Slots, Thomas E. Rams
Journal: Periodontology 2000 (2023)

Abstract Localized juvenile (aggressive) periodontitis starts at puberty in otherwise healthy individuals and involves the proximal surfaces of permanent incisors and first molars. The disease destroys a sizeable amount of periodontal bone within a few months despite minimal dental plaque and gingival tissue inflammation. Cytomegalovirus and Epstein–Barr virus, as well as the two main periodontopathic bacteria Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis , are linked to juvenile periodontitis. Juvenile periodontitis‐affected teeth show cementum hypoplasia. We hypothesize that an active herpesvirus infection, at the time of root formation, hampers cementum formation and, at puberty, herpesvirus reactivation triggers an upgrowth of bacterial pathogens which produce rapid periodontal destruction on teeth with a defective periodontium. A pathogenic interaction between active herpesviruses and bacterial pathogens can potentially explain the etiology and incisor‐first molar destructive pattern of juvenile periodontitis. Effective treatment of juvenile periodontitis may target the herpesvirus‐bacteria co‐infection.
Estimated protection against COVID-19 based on predicted neutralisation titres from multiple antibody measurements in a longitudinal cohort, France, April 2020 to November 2021
Authors: Tom Woudenberg, Laurie Pinaud, Laura Garcia, Laura Tondeur, Stéphane Pelleau, Alix De Thoisy, Françoise Donnadieu, Marija Backovic, Mikaël Attia, Nathanael Hozé, Cécile Duru, Aymar Davy Koffi, Sandrine Castelain, Marie-Noelle Ungeheuer, Sandrine Fernandes Pellerin, Delphine Planas, Timothée Bruel, Simon Cauchemez, Olivier Schwartz, Arnaud Fontanet, Michael White
Journal: Eurosurveillance (2023)

Background The risk of SARS-CoV-2 (re-)infection remains present given waning of vaccine-induced and infection-acquired immunity, and ongoing circulation of new variants. Aim To develop a method that predicts virus neutralisation and disease protection based on variant-specific antibody measurements to SARS-CoV-2 antigens. Methods To correlate antibody and neutralisation titres, we collected 304 serum samples from individuals with either vaccine-induced or infection-acquired SARS-CoV-2 immunity. Using the association between antibody and neutralisation titres, we developed a prediction model for SARS-CoV-2-specific neutralisation titres. From predicted neutralising titres, we inferred protection estimates to symptomatic and severe COVID-19 using previously described relationships between neutralisation titres and protection estimates. We estimated population immunity in a French longitudinal cohort of 905 individuals followed from April 2020 to November 2021. Results We demonstrated a strong correlation between anti-SARS-CoV-2 antibodies measured using a low cost high-throughput assay and antibody response capacity to neutralise live virus. Participants with a single vaccination or immunity caused by infection were especially vulnerable to symptomatic or severe COVID-19. While the median reduced risk of COVID-19 from Delta variant infection in participants with three vaccinations was 96% (IQR: 94–98), median reduced risk among participants with infection-acquired immunity was only 42% (IQR: 22–66). Conclusion Our results are consistent with data from vaccine effectiveness studies, indicating the robustness of our approach. Our multiplex serological assay can be readily adapted to study new variants and provides a framework for development of an assay that would include protection estimates.